CN100526293C - 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof - Google Patents
2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof Download PDFInfo
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- CN100526293C CN100526293C CNB2006101391313A CN200610139131A CN100526293C CN 100526293 C CN100526293 C CN 100526293C CN B2006101391313 A CNB2006101391313 A CN B2006101391313A CN 200610139131 A CN200610139131 A CN 200610139131A CN 100526293 C CN100526293 C CN 100526293C
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Abstract
The present invention belongs to the field of medicine technology, and discloses magnesium 2, 5-dihydroxy benzene sulfonate and its hydrate and their preparation process and application in improving microcirculation and protecting blood vessel. The salt magnesium 2, 5-dihydroxy benzene sulfonate and its hydrate have obviously raised stability in high temperature, illuminating and high humidity and other conditions, convenient production and clinical application and broad application foreground.
Description
1, technical field
The present invention relates to 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof, its preparation method and in the application that improves aspect capillary blood vessel circulation and the vascular protection belong to medical technical field.
2, background technology
Dobesilate Calcium (Dobesilate Calcium) is 2, the monohydrate of 5-dihydroxy benzenes sulfonic acid calcium, be French Carroin company in Initial Public Offering in 1971, Dobesilate Calcium was written into European Pharmacopoeia in 1997, be written into British Pharmacopoeia in 1998, domesticly June calendar year 2001 this medicine introduced to the market.Dobesilate Calcium is the capillary blood vessel circulation activator or the vasoprotector of widespread use; have hypoglycemic; press down platelet aggregation; reduce pharmacological actions such as capillary permeability; the diseases such as retinopathy that diabetes are caused have obvious restraining effect and change reverse action especially, are the unique matured products of diabetic retinopathy.
The Dobesilate Calcium of existing listing is 2, and the monohydrate of 5-dihydroxy benzenes sulfonic acid calcium is an ideal disease of capillaries medicine comparatively, but it is easy to change, rotten to meet light, water absorbability is arranged, and poor stability brings great inconvenience for production, storage, circulation and use.Therefore, improve 2, the stability of the monohydrate of 5-dihydroxy benzenes sulfonic acid calcium becomes present problem demanding prompt solution.
3, summary of the invention
In order to address the above problem, the invention provides 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof, its preparation method and in the application that improves aspect capillary blood vessel circulation and the vascular protection.Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof are compared with the calcium salt of listing, and under the test conditions of 40 ℃ of high temperature, 60 ℃, high humidity 92.5% and illumination 4500LX, stability has had the raising of highly significant, and solvability also increases.
Concrete technical scheme of the present invention is as follows:
The invention provides 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof also provide the preparation method and the application of these compounds in addition.
2, the structural formula of 5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof is as follows:
Wherein, n=0,1,2,3,4,5,6.
Of the present invention 2, the hydrate of 5-dihydroxy benzenes sulfonic acid magnesium can be monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate, is preferably monohydrate and tetrahydrate.Through contriver a large amount of shaker test, the result proves that the tetrahydrate of above-claimed cpd has better stability and improves significantly aspect hygroscopic property, therefore tetrahydrate more preferably.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof can prepare by following method: with 2,5-dihydroxy benzenes sulfonic acid potassium is starting raw material, through the storng-acid cation exchange resin exchange, generate 2, the 5-dihydroxy benzenes sulfonic acid aqueous solution, underpressure distillation charges into nitrogen after concentrating, sealing is kept in Dark Place, again with 2, and the 5-dihydroxy benzenes sulfonic acid aqueous solution and corresponding alkaline magnesium-containing compound salify, reaction solution is concentrated into dried, get crude product 2, the 5-dihydroxy benzenes sulfonic acid magnesium is with crude product solid chemical compound washing with acetone, filter, solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol, dry 2 under different condition, 5-dihydroxy benzenes sulfonic acid magnesium or its hydrate.Described alkaline magnesium-containing compound is magnesium oxide, magnesiumcarbonate, magnesium hydroxide, Magnesium hydrogen carbonate.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and tetrahydrate thereof specifically can prepare by following method: get 2,5-dihydroxy benzenes sulfonic acid potassium, be dissolved in water, join in the strong acidic ion resin exchange column and exchange, collect required component 2,5-dihydroxy benzenes sulfonic acid solution, 50 ℃ of following underpressure distillation of gained solution charge into nitrogen after concentrating, and sealing is kept in Dark Place standby; Measure make 2,5-dihydroxy benzenes sulfonic acid solution, stirring state slowly adds corresponding alkaline magnesium-containing compound (magnesium oxide, magnesiumcarbonate, magnesium hydroxide or Magnesium hydrogen carbonate) stirring and dissolving down, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium hydrate crude product, with crude product solid chemical compound washing with acetone, filter, in the mixing solutions of chloroform and methyl alcohol, get pure product with silica gel adsorption; The pure product of gained under 1.33kPa pressure, 120 ℃ of conditions dry 24 hours 2, the 5-dihydroxy benzenes sulfonic acid magnesium; The pure product of gained under 1.33kPa pressure, 80 ℃ of conditions dry 4 hours 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
By 2,5-dihydroxy benzenes sulfonic acid preparation 2, the chemical equation of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate is as follows:
Magnesium oxide in the above-mentioned reaction formula can use alkaline magnesium-containing compound such as magnesiumcarbonate, magnesium hydroxide or Magnesium hydrogen carbonate to replace.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof can be mixed and made into clinically arbitrary or pharmaceutically acceptable formulation with auxiliary material, and preferred oral preparation or injection are applied to the patient who needs this treatment in the mode of oral or administered parenterally.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet is based on oral ordinary tablet, and other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill comprises dripping pill, sugar-pill, piller etc.Granule can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.
When being used for administered parenterally, can be made into injection.Injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid comprises sterile solution type injection liquid, emulsion-type injection liquid, suspension type injection liquid etc., can be used for intramuscularly, intravenous injection, intravenous drip etc.Injectable sterile powder is sterilized powder or aseptic block, and available solvent crystallization, spray-drying process or freeze-drying etc. make.
Of the present invention 2, the preparation of 5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof can adopt the ordinary method production in the existing pharmacy field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof are when making oral preparations, and selectable weighting agent has: starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Selectable tackiness agent has: Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Selectable disintegrating agent has: dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Selectable lubricant has: Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof in order to increase its solubleness, can add solubilizing agent such as Polysorbate 80 when making injection.Can add the isotonic regulator that is used to regulate osmotic pressure in the transfusion, for example, sodium-chlor, chlorination, magnesium chloride, calcium chloride, Sodium.alpha.-hydroxypropionate, glucose, Xylitol, sorbyl alcohol and dextran etc., preferred sodium-chlor or glucose.Can add vehicle in the powder pin, for example, N.F,USP MANNITOL, glucose etc.
The present invention is further claimed of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof in preparation as the application in the medicine of capillary blood vessel circulation activator and vasoprotector.Of the present invention 2, the perviousness and the fragility of capillary wall can be adjusted and improve to 5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof, can suppress biologically active substances such as bradykinin again, be mainly used in the disease of capillaries that the multiple reason of treatment causes, as diseases such as diabetic retinopathy, varix, phlebitis, brain spasm, pruritic dermatitises.This product bioavailability height, toxicity is lower, and the therapeutic index height is an ideal disease of capillaries medicine comparatively.
According to expert introduction, diabetes are vitamin B6, these two kinds of material wants of magnesium and cause, the people of all trouble diabetes, magnesium content in the blood is low especially, therefore Mg supplementation can reduce the requirement of health to B6, reduce the generation of toxic substance xanthurenic acid simultaneously, also should have some improvement the complication of diabetes.Therefore, of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof are compared with calcium salt, and the retinopathy that diabetes are caused should have better effect.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and tetrahydrate thereof and gone on the market 2, the monohydrate of 5-dihydroxy benzenes sulfonic acid calcium is compared, solubleness makes moderate progress, and the results are shown in Table 1.
Table 1 solubleness relatively
2 of compound of the present invention and listing, 5-dihydroxy benzenes sulfonic acid calcium monohydrate is compared, and under high temperature, high humidity and strong illumination condition better stability is arranged.Below be 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate, 2,5-dihydroxy benzenes sulfonic acid magnesium and 2,5-dihydroxy benzenes sulfonic acid calcium monohydrate is placed 10 days stability result under 40 ℃ of high temperature, 60 ℃, the condition of illumination 4500Lx, high humidity 92.5%, investigate index and be mainly proterties and content, the results are shown in Table 2.
Table 2 stability is (10 days) relatively
The presentation of results of above table 2,2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate, 2,5-dihydroxy benzenes sulfonic acid magnesium and 2,5-dihydroxy benzenes sulfonic acid calcium monohydrate compares, and stability has had significant raising under conditions such as high temperature, illumination and high humidity, beyond thought effect occurred.
Of the present invention 2,5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof compared with prior art have following beyond thought advantage:
(1) provides a kind of pharmaceutically applicable 2 first, 5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof (especially tetrahydrate), compare with the calcium salt of listing, under the test conditions of 40 ℃ of high temperature, 60 ℃, high humidity 92.5% and illumination 4500LX, stability has had raising extremely significantly, and especially hygroscopic property has clear improvement;
(2) provide new 2 first, the preparation method of 5-dihydroxy benzenes sulfonic acid magnesium and hydrate thereof, its preparation technology is simple, medicine purity height, steady quality;
(3) provided by the invention 2,5-dihydroxy benzenes sulfonic acid magnesium hydrate especially tetrahydrate is compared with calcium salt, and the retinopathy that diabetes are caused has better effect.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 12, the preparation of 5-dihydroxy benzenes sulfonic acid solution
Get 2,5-dihydroxy benzenes sulfonic acid potassium 100g (439mmol), use the 400ml water dissolution, join then in the strong acidic ion resin exchange column and exchange, collect required component 2,5-dihydroxy benzenes sulfonic acid solution charges into nitrogen after 50 ℃ of following underpressure distillation of gained solution are concentrated into 300ml, and sealing is kept in Dark Place standby.
Embodiment 22, the preparation of 5-dihydroxy benzenes sulfonic acid magnesium
It is prepared 2 to measure embodiment 1, and 5-dihydroxy benzenes sulfonic acid solution 10ml, stirring state slowly add the solid oxidation magnesium dust down, stirring and dissolving, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium crude product.Crude product solid chemical compound washing with acetone filters, and solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol.Pure product under 1.33kPa pressure, 120 ℃ of conditions dry 24 hours 2, the 5-dihydroxy benzenes sulfonic acid magnesium.
Content (HPLC): 99.7% (in anhydride)
Ultimate analysis (C
12H
10O
10S
2Mg)
Molecular weight: 402.6
Measured value: C:35.75%; H:2.48%; Mg:6.06%; S:15.95%
Theoretical value: C:35.80%; H:2.50%; Mg:6.04%; S:15.93%
1H—NMR(600MHz，CDCl
3)：δ：5.02(4H，w)，6.63(2H，d)，6.85(2H，d)，7.24(2H，s)IR(KBr)cm
-1：3055，1976，1765，1628，1186，758，704
Embodiment 32, the preparation 1 of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate
It is prepared 2 to measure embodiment 1, and 5-dihydroxy benzenes sulfonic acid solution 10ml, stirring state slowly add the solid oxidation magnesium dust down, stirring and dissolving, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium crude product.Crude product solid chemical compound washing with acetone filters, and solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol.Pure product under 1.33kPa pressure, 80 ℃ of conditions dry 4 hours 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
Content (HPLC): 99.6% (in anhydride)
Ultimate analysis (C
12H
10O
10S
2Mg4H
2O)
Molecular weight: 474.7
Measured value: C:30.29%H:3.86%S:13.48%Mg:5.15%
Theoretical value: C:30.36%H:3.82%S:13.51%Mg:5.12%
1H—NMR(600MHz，CDCl
3)：δ：5.05(4H，w)，6.64(2H，d)，6.85(2H，d)，7.26(2H，s)IR(KBr)cm
-1：3051，1974，1765，1625、1185，755，703
The sample of getting the present embodiment preparation carries out thermal weight loss and differential thermal analysis: experimental result shows, the sample of this law preparation does not have weightlessness before 140 ℃, be no free-water or volatile solvent in the sample, 100 ℃～200 ℃ weightlessness is about 15.84%, this with sample in to contain result's (theoretical value 15.2%) of 4 molecular crystal water consistent; Differential thermal analysis result shows: this sample has endotherm(ic)peak at 172.5 ℃, contains crystal water or recrystallisation solvent in the interpret sample; Weight loss on drying and water analysis: the sample of present embodiment preparation is dried to constant weight at 120 ℃, and subtracting weight loss is 15.82%; Press cassette aquametry mensuration moisture wherein in addition, the moisture determination result is 15.80%.Two kinds of unanimities as a result show and only contain moisture in the sample, do not contain other solvents.
Comprehensive ultimate analysis, thermal weight loss and differential thermal analysis result can prove the crystal water that contains 4 molecules in the sample.
Embodiment 42, the preparation 2 of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate
It is prepared 2 to measure embodiment 1, and 5-dihydroxy benzenes sulfonic acid solution 10ml, stirring state slowly add 1N magnesium hydroxide solution down, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium crude product.Crude product solid chemical compound washing with acetone filters, and solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol.Pure product under 1.33kPa pressure, 80 ℃ of conditions dry 4 hours 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
Content (HPLC): 99.8% (in anhydride)
Get the sample of present embodiment preparation and measure crystal water: thermal weight loss and differential thermal analysis, 100 ℃～200 ℃ weightlessness about 15.86% by embodiment 3 methods; Differential thermal analysis, 172.5 ℃ have endotherm(ic)peak, contain crystal water or recrystallisation solvent in the interpret sample; Weight loss on drying and water analysis, 120 ℃ are dried to constant weight, and subtracting weight loss is 15.83%; Press cassette aquametry mensuration moisture wherein in addition, the moisture determination result is 15.81%.Two kinds of unanimities as a result show and only contain moisture in the sample, do not contain other solvents.
Comprehensive ultimate analysis, thermal weight loss and differential thermal analysis result can prove the crystal water that contains 4 molecules in the sample.
Embodiment 52, the preparation 3 of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate
It is prepared 2 to measure embodiment 1, and 5-dihydroxy benzenes sulfonic acid solution 10ml, stirring state slowly add the solid carbonic acid magnesium dust down, stirring and dissolving, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium crude product.Crude product solid chemical compound washing with acetone filters, and solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol.Pure product under 1.33kPa pressure, 80 ℃ of conditions dry 4 hours 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
Content (HPLC): 99.5% (in anhydride)
Get the sample of present embodiment preparation and measure crystal water: thermal weight loss and differential thermal analysis, 100 ℃～200 ℃ weightlessness about 15.85% by embodiment 3 methods; Differential thermal analysis, 172.5 ℃ have endotherm(ic)peak, contain crystal water or recrystallisation solvent in the interpret sample; Weight loss on drying and water analysis, 120 ℃ are dried to constant weight, and subtracting weight loss is 15.84%; Press cassette aquametry mensuration moisture wherein in addition, the moisture determination result is 15.82%.Two kinds of unanimities as a result show and only contain moisture in the sample, do not contain other solvents.
Comprehensive ultimate analysis, thermal weight loss and differential thermal analysis result can prove the crystal water that contains 4 molecules in the sample.
Embodiment 62, the preparation 4 of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate
It is prepared 2 to measure embodiment 1, and 5-dihydroxy benzenes sulfonic acid solution 10ml, stirring state slowly add the solid hydrogen magnesium oxide powder down, stirring and dissolving, until about pH=2, reaction solution is concentrated into dried, baby pink 2,5-dihydroxy benzenes sulfonic acid magnesium crude product.Crude product solid chemical compound washing with acetone filters, and solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol.Pure product under 1.33kPa pressure, 80 ℃ of conditions dry 4 hours 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
Content (HPLC): 99.7% (in anhydride)
Get the sample of present embodiment preparation and measure crystal water: thermal weight loss and differential thermal analysis, 100 ℃～200 ℃ weightlessness about 15.83% by embodiment 3 methods; Differential thermal analysis, 172.5 ℃ have endotherm(ic)peak, contain crystal water or recrystallisation solvent in the interpret sample; Weight loss on drying and water analysis, 120 ℃ are dried to constant weight, and subtracting weight loss is 15.81%; Press cassette aquametry mensuration moisture wherein in addition, the moisture determination result is 15.82%.Two kinds of unanimities as a result show and only contain moisture in the sample, do not contain other solvents.
Comprehensive ultimate analysis, thermal weight loss and differential thermal analysis result can prove the crystal water that contains 4 molecules in the sample.
The preparation of embodiment 7 The compounds of this invention capsules
Prescription 1:
Prescription 2:
Preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with 2,5-dihydroxy benzenes sulfonic acid magnesium or its tetrahydrate, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, and the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, micropowder silica gel, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 The compounds of this invention tablets
Prescription 1:
Prescription 2:
Preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with 2,5-dihydroxy benzenes sulfonic acid magnesium or its tetrahydrate, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, and the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 The compounds of this invention granules
Prescription 1:
Prescription 2:
Preparation technology:
1) it is standby sucrose to be pulverized 100 mesh sieves.With 2, it is standby that 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate was pulverized 100 mesh sieves.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) with 2, the method that 5-dihydroxy benzenes sulfonic acid magnesium or its tetrahydrate and Icing Sugar progressively increase with equivalent mixes, and adding 2%HPMC60% ethanolic soln is an amount of, stirs, and makes suitable softwood,
4) cross 20 mesh sieve system particles.
5) particle is dried under 60 ℃ condition.
6) dried particle is crossed the whole grain of 18 mesh sieves.
7) sampling, the content of main ingredient is determined loading amount in the work in-process chemical examination particle.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 The compounds of this invention dispersible tablets
Prescription 1:
Prescription 2:
Preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) with 2,5-dihydroxy benzenes sulfonic acid magnesium or its tetrahydrate, pregelatinized Starch, polyvinylpolypyrrolidone, Microcrystalline Cellulose, hydroxypropylcellulose mix, and it is an amount of to add entry, stirs, and makes suitable softwood.
4) 20 mesh sieve system particles.
5) particle is dried under 60 ℃ condition.
6) dry good particle adds Magnesium Stearate, silicon-dioxide and cross-linked polyvinylpyrrolidone, crosses the whole grain of 18 mesh sieves, mixes.
5) sampling, the work in-process chemical examination.
6) the sheet weight sheet of determining according to chemical examination.
7) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 11 The compounds of this invention aqueous injections
Prescription 1:
Prescription 2:
Preparation technology:
1) container of at first dosing being used, ampoule, the plant-scale equipment, instrument etc. carry out pre-treatment.
2) take by weighing raw material by recipe quantity.
3) with 2, stirring and dissolving in the water for injection of 5-dihydroxy benzenes sulfonic acid magnesium or its tetrahydrate adding dosing amount 80%, the needle-use activated carbon temperature control of adding 0.1% stirred filtering decarbonization 10 minutes for 50 ℃.
4) the pH value of survey solution adds water and is settled to cumulative volume.
5) with the filtering with microporous membrane of 0.45 μ m.
6) clarity of inspection solution.
7) inspection of semifinished product.
8) the qualified back of inspection of semifinished product sealing by fusing is in ampoule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.05% methylene blue solution hunts leak.
11) warehouse-in is examined, packed to finished product entirely.
Claims (5)
1, as follows 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate:
Wherein, n=4.
2, according to claim 12, the preparation method of 5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate, it is characterized in that, with 2,5-dihydroxy benzenes sulfonic acid potassium is starting raw material, exchanges through storng-acid cation exchange resin, generate 2, the 5-dihydroxy benzenes sulfonic acid aqueous solution, underpressure distillation charges into nitrogen after concentrating, and sealing is kept in Dark Place; Again with 2, the 5-dihydroxy benzenes sulfonic acid aqueous solution and magnesium oxide, magnesiumcarbonate, magnesium hydroxide salify, reaction solution is concentrated into dried, get crude product, with crude product solid chemical compound washing with acetone, filter, solid gets pure product with silica gel adsorption in the mixing solutions of chloroform and methyl alcohol, dry under certain condition 2,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate.
3, pharmaceutically acceptable formulation is characterized in that, described 2 by claim 1,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate and auxiliary material are mixed and made into.
4, the described pharmaceutically acceptable formulation of claim 3 is oral preparations or injection.
5, according to claim 12,5-dihydroxy benzenes sulfonic acid magnesium tetrahydrate in preparation as the application in the medicine of capillary blood vessel circulation activator and vasoprotector.
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| CN102219715B (en) * | 2011-04-26 | 2013-11-13 | 北京振东光明药物研究院有限公司 | Method for preparing medicinal high-purity calcium dobesilate |
| CN102920690A (en) * | 2011-08-12 | 2013-02-13 | 王康俊 | Chemical medicine for treating cerebral-cardio vascular diseases |
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Non-Patent Citations (4)
| Title |
|---|
| 2, 5-二羟基苯磺酸钙治疗糖尿病肾病的作用机理. 张晓倩等.山东医药，第44卷第4期. 2004 |
| 2, 5-二羟基苯磺酸钙治疗糖尿病肾病的作用机理. 张晓倩等.山东医药，第44卷第4期. 2004 * |
| Dobesilate enhances endothelial nitricoxidesynthase-activityinmacro- and microvascular endothelialcells. Christoph Suschek,et al.British Journal of Pharmacology,Vol.122 . 1997 |
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